The extracellular signal regulated protein kinase (ERK) pathway is one of the intracellular signaling systems involved in neuronal development, survival, and long-term synaptic plasticity. Our previous studies reveal that treatment of rats or mice with antimanic mood-stabilizers, lithium and valproate, in clinically relevant manners activate the ERK pathway in prefrontal cortex and hippocampus. In addition, lithium and valproate promote the molecular and cellular function of ERK pathway such as BDNF and Bcl-2 expressions, neurogenesis, and neuronal survival. In animal behavioral studies we found that chemical inhibition of brain ERK pathway in rats reduces immobility in the forced swim test and increased locomotive/explorative activity in the large open field test. Our studies also showed that ERK1 (one of two ERK subtypes) knockout mice are with brain regional specific functional deficit of the ERK pathway and exhibit reduced immobility in the forced swim test, increased activity in the open field test, persistently increased home-cage wheel running activity for at least 30 days, and enhanced response to psychostimulants. Recently we examined the role of the ERK pathway as a behavioral modulator in left anterior cingulate cortex, one of the brain regions implicated in the pathophysiology of mood disorders by human brain imaging and postmortem studies. In vivo gene delivery, brain stereotaxic surgery, chronic brain regional infusion, and behavioral tests were performed. Rats chronically infused with an ERK pathway inhibitor directly to left anterior cingulate cortex showed significant reduction of immobility in the forced swim test, increase in locomotive activities in the open field test, and enhancement of locomotive response to amphetamine. To further verify these findings, we developed a method to regionally express dominated negative ERK1 (to inhibit function of endogenous ERK) in left anterior cingulate cortex by injection of lentiviral vectors. Compared to the controls, rats injected with dominant negative ERK1 expression vector showed a trend of reduced immobility in the forced swim test, significant increases in activity in the open field test, and significant increases in time spend in open arms in the elevated plus maze test. These rats also consumed more sweetened water in the sucrose and saccharin preference tests compared to control rats. Together, the body of data supports the role of the anterior cingulate in modulation of behaviors relevant to mood disorders; furthermore, the ERK pathway in the left anterior cingulate cortex is one of intracellular loops of neuronal circuitry that mediates hedonic and locomotive/explorative activities. The brain regional specific roles of the ERK pathway in the pathophysiology of mood disorders and in the therapeutic actions of antimanic agents are worthy for the further investigations.